Search

The effects of H290/51, a novel indenoindole derivative inhibitor of lipid peroxidation, on ultrastructural changes during cardiac ischemia-reperfusion injury were investigated. Langendorff-perfused rat hearts were exposed to 30 minutes of global ischemia followed by 20 minutes of reperfusion: Group A: Control hearts with standard buffer perfusion with vehicle added. Group B: H290/51 (10(-6) mol/l) added to buffer throughout stabilisation and reperfusion. In an additional Group C, where hearts were given H290/51, but not subjected to ischemia, the ultrastructure was preserved till the end of reperfusion. Absolute volumes and calculated volume fractions (Vv) of tissue and subcellular components were assessed with quantitative stereologic morphometry. After ischemia the increase in volume of extracellular interstitium was inhibited by H290/51 (247 +/- 80 vs. 159 +/- 50 microl, mean +/- SD, groups A and B, respectively, p

In studies of preconditioning, a variety of models have been used. The aim of the present study was to find the optimal preconditioning model for preservation of cardiac function during reperfusion of globally ischaemic, Langendorff-perfused rat hearts. Cardiac function was assessed by the occurrence of severe reperfusion arrhythmias (ventricular fibrillation or asystolia), heart rate (HR), left ventricular systolic (LVSP), end diastolic (LVEDP), and developed pressures (LVDP = LVSP - LVEDP), as well as coronary flow (CF). Series 1 (n = 17) in each group: control perfusion for 20 min without preconditioning or 2 episodes of 2, 3, 4, or 5 min of ischaemia, each followed by 5 min reperfusion, before 25 min ischaemia and 60 min reperfusion. Preconditioning reduced the incidence of reperfusion arrhythmias, attenuated the reperfusion-induced increase of LVEDP, and increased CF, but did not influence LVSP, LVDP, or rate x pressure-product (RPP = LVSP x HR) during reperfusion. The greatest effect was found by 2 min ischaemia and 5 min reperfusion. In series 2 (n = 17 in each group) control perfusion for 7 or 28 min, or preconditioning with 1-4 episodes of 2 min ischaemia and 5 min reperfusion before 35 min ischaemia and 60 min reperfusion were compared. Reduction of severe reperfusion arrhythmias and LVEDP elevation, as well as improvement of CF, LVDP, and HR in preconditioned hearts were observed in series 2. Optimal cardioprotection was achieved by only one episode of preconditioning. In conclusion, preconditioning before global ischaemia improved cardiac function during reperfusion of isolated rat hearts. The most marked effects were reduction of severe reperfusion arrhythmias and attenuation of diastolic dysfunction. Although all preconditioning models employed were cardioprotective, 1 episode of 2 min ischaemia provided optimal protection.

The effects of methylprednisolone (MP) on the acute airway and pulmonary vascular responses induced by reactive oxygen species (ROS) were investigated in isolated, plasma-perfused rat lungs. ROS were generated by adding xanthine oxidase and hypoxanthine to the perfusate. MP was administered in 3 different ways: 1. Added to the perfusate (1 mg*ml-1) 5 min prior to xanthine oxidase and hypoxanthine, 2. Given as intraperitoneal injections (40 mg*kg-1) to lung donor rats 12 and 2 hours prior to the experiments, or 3. Combining 1 and 2. The lungs were perfused at constant volume inflow (15 ml*min-1). Pulmonary arterial pressure and transpulmonary pressure were followed for 30 min after addition of xanthine oxidase and hypoxanthine. ROS induced a powerful, acute broncho- and vasoconstriction, which was inhibited by addition of MP to the perfusate. Pretreatment with MP also inhibited the vascular and airway responses. Adding MP to the perfusate of pretreated lungs further reduced the ROS-induced smooth muscle constriction. In conclusion, MP inhibits vasoconstriction and bronchoconstriction induced by ROS in isolated rat lungs.

The role of histamine in cardiac physiology and pathophysiology is not clarified, but is dependent on species. The effects of exogenous histamine in Langendorff-perfused rat hearts were investigated. 1 mM, 100, 10, 1 and 0.1 microM of histamine (n = 7 each) as 15 min infusions were employed in a dose-response study, and compared to control perfused hearts (n = 7). In another experimental series, 100 microM histamine (n = 15) was added during reperfusion after 25 min global ischemia, and compared to control ischemia-reperfusion (n = 15). The maximal response to histamine in the dose-response study (100 microM) was an increase of left ventricular developed pressure to 126 +/- 8% of initial value (mean +/- SEM, p0.04), and increase of coronary flow to 152+6% (p0.02) after 5 min infusion. 100 microM histamine did not significantly influence heart rate or rhythm. The lowest concentration (0.1 microM) did not have effects cardiac performance. Reperfusion with histamine for 2 min after ischemia reduced left ventricular developed pressure to 68 +/- 10% of initial value versus 116+17% in ischemic controls (p0.05), and increased left ventricular end-diastolic pressure to 24 +/- 8 mmHg compared to 6 +/- 2 mmHg in controls (p0.04). Left ventricular pressures were similar in hearts reperfused with histamine and in ischemic controls for the rest of the observation. Coronary flow increased during reperfusion in hearts given histamine. Histamine had a dose-dependent positive inotropic and vasodilatory effect in isolated rat hearts. Exogenous histamine had only minor effects on post-ischemic cardiac function.

The role of arachidonic acid metabolites in the cardiac effects of toxic oxygen metabolites (TOM) was investigated in buffer-perfused rat hearts (Langendorff model). Hydrogen peroxide (H 2 O 2 , 200 μM) was given for 10 min to generate TOM, followed by 30 min recovery. H 2 O 2 reduced left ventricular developed pressure (LVDP), increased left ventricular end-diastolic pressure (LVEDP), and increased coronary flow (CF). The hydroxyl radical scavenger thiourea inhibited the H 2 O 2 -induced effects. Perfusion with three lipoxgenase inhibitors, AA861, BWA4C, and diethylcarbamazine, in adition to H 2 O 2 , augmented the decrease of LVDP and the increase of LVEDP induced by H 2 O 2 . The cyclooxygenase inhibitor indomethacin had the same effects. The H 2 O 2 -induced increased in CF was not influenced by diethylcarbamazine, but inhibited by all other drugs. Control perfusion with drugs alone did not influence cardiac function. In conclusion, inhibition of lipoxygenase and cyclooxygenase augmented the depression of cardiac function induced by TOM. Leukotrienes and prostanoids appear to be protective against H 2 O 2 -induced cardiac injury.

Tissue plasminogen activator (t-PA) is a marker of endothelial cell injury or activation. The release of t-PA from isolated rat hearts (Langendorff model) subjected to ischemia-reperfusion or reactive oxygen intermediates (ROI) generated by H2O2 was investigated. H2O2 (200 microM) increased t-PA activity in the coronary effluent to 305 +/- 84% of initial value (mean +/- SEM, p0.04 vs controls) at the end of a 10 min intervention. The hydroxyl radical scavenger thiourea (10 mM) only partially inhibited the increase (175 +/- 27%, p0.01 compared to controls). 20 min normothermic ischemia increased t-PA activity to 416 +/- 108% (p0.005 compared to controls) at the start of reperfusion. In conclusion, cardiac injury by ischemia-reperfusion or ROI increases release of t-PA.

In a double-blind study 18 patients were randomized to receive a daily dietary supplement of concentrated ethyl ester compound of n-3 fatty acids or placebo (corn oil) for at least 6 weeks before coronary bypass surgery. Three-fold increase of serum eicosapentaenoic acid and 20% reduction of triglyceride levels were found preoperatively in the n-3 group, while the two groups were similar as regards monocyte and platelet counts, mean platelet volume and monocyte activation as expressed by thromboplastin activities. For determination of transcardiac gradients, coronary sinus and aortic blood were sampled preoperatively 5, 10 and 30 minutes after release of the aortic cross-clamp. In both patient groups the monocyte count was lower in coronary sinus than in aortic blood at 5 and 10 minutes, but the differences were not significant. The platelet counts showed no significant change. In vitro stimulation of monocytes, however, evoked significantly (p0.05) less thromboplastin activity in coronary sinus blood than in aortic blood at all three sampling times, without significant intergroup difference. The monocytes most sensitive to activation presumably were trapped in the reperfused myocardium, and this sequestration was not hindered by pretreatment with n-3 fatty acids.

Polymorphonuclear granulocytes (PMN) are suggested mediators of myocardial ischemia-reperfusion injury. We have previously shown that activated PMN producing oxygen free radicals (OFR) in the coronary circulation are cardiodepressive. OFR may induce lipid peroxidation and production of eicosanoids. We have investigated the influence of cyclo-oxygenase and lipoxygenase inhibitors on the effects of activated, OFR producing PMN in the Langedorff rat heart model. Left ventricular developed pressure (VLDP) was measured by a balloon in the left ventricle. Human PMN and drugs were given into the aortic cannula for 10 min and the hearts were observed for 30 min thereafter. After infusion for 5 min OFR production in the cellular infusate was measured at the level of the aortic cannula by a chemiluminescence (CL) technique. Phorbol 12-myristate 13-acetate (PMA)-activated PMN ( n = 8), produced a CL response of 27649 ± 11048 counts (mean ± s.e.m. ), and reduced coronary flow (CF) to 53 ± 6% (mean ± s.e.m. ) and LVDP to 38 ± 9% of baseline values at the end of the observation period. Ibuprofen ( n = 6), a cyclooxygenase (CO) inhibitor, neither influenced the CL response (31915 ± 7563) of activated PMN, nor the reduction of CF and LVDP at this time. Although both BW 755C ( n = 7), a dual inhibitor of CO and lipoxygenase (LO) (CF:90 ± 4%, LVDP:99 ± 6%) and diethylcarbamazine (DCM) ( n = 8), a LO inhibitor (CF:88 ± 11%, LVDP:87 ± 4%), significantly inhibited the cardiodepressive effects of activated PMN. BW 755C alone abolished the CL response (431 ± 158 counts), whereas DCM had no effect on CL (30105 ± 1698 counts). In conclusion, the injurious effects of activated leukocytes in the coronary circulation seem to be mediated through LO products.

Ischaemic preconditioning (IPC) has been demonstrated to protect heart function and viability, but has been predominantly studied in male animals.We studied a possible influence of sex and oestrogen for protection in IPC. Infarct size and heart function after 40 min global ischaemia and 60 min reperfusion with or without preceding classic IPC was investigated in Langendorff-perfused hearts. Hearts were harvested from 10-week-old male and female C57BL6 mice with or without gonadectomy 6 weeks earlier, or gonadectomy and substitution with 17 beta-oestradiol for 4 weeks (n = 104).Classic IPC reduced depression of left ventricular developed pressure (P0.01), attenuated the increase of end-diastolic pressure (P0.01), and reduced infarct size (P0.01) in hearts of untreated male mice, but failed to protect untreated females which had improved functional recovery and smaller infarctions than untreated males. After gonadectomy of female mice, developed pressure was reduced (P0.01) and infarct size increased (P0.01) compared with normal females, with no protection of preconditioning. The changes were not reversed by 17 beta-oestradiol substitution. In hearts of gonadectomized males, the post-ischaemic increase of end-diastolic pressure was attenuated (P0.01), and enhanced after substitution with 17 beta-oestradiol (P0.01). The preconditioning effect disappeared after gonadectomy and gonadectomy with substitution in male mice.There is a sex difference in evoking preconditioning in male and female mice which is only partially dependent on sex hormones.

The isolated, buffer-perfused heart is probably the most widely used model in experimental heart research, and the coronary effluent is often analysed for markers of myocardial injury. Adsorption to surrounding materials may be a serious problem of protein measurements in solutions with low protein concentrations. The aims of the present study were to investigate the importance of the preanalytical phase when measuring cardiac troponin T (cTnT) in a buffer perfusate and to investigate whether addition of albumin to the effluent might increase recovery of cTnT and improve the assay. Coronary effluent was collected in tubes of different materials and in tubes with 40 g/L bovine albumin, and then frozen. cTnT was analysed at different time points after withdrawal from the freezer. cTnT was 2.3-119 times higher in effluent with albumin. In effluent without albumin, cTnT concentration declined to 2% of the initial concentration after two episodes of freezing and thawing. The cTnT loss could not be prevented by using polystyrene or siliconized glass, but was partially inhibited in effluent with albumin. Furthermore, creatine kinase and lactate dehydrogenase levels were higher in effluent with albumin. The within-series coefficient of variation for cTnT was markedly improved when using effluent with albumin.

Exposure of rats to hyperoxia before organ harvesting protected their isolated hearts against global ischaemia-reperfusion injury in a previous study. The present study investigates whether hyperoxia influences vasomotor function and regional ischaemia of the heart. Isolated rings of the thoracic aorta were obtained from rats immediately or 24 h after in vivo exposure to 60 min of hyperoxia (95% O2), and the in vitro dose-response to phenylephrine (PHE), prostaglandin F2alpha (PGF2alpha) and endothelin-1 (ET-1), acetylcholine (Ach) and sodium nitroprusside (SNP) was assessed. Hyperoxia in vivo increased the relaxation of aortic rings to Ach and SNP, while it delayed contraction to PHE. The effect was more evident when the vessels were harvested immediately rather than 24 h after hyperoxic exposure. In separate experiments rat hearts were isolated immediately after hyperoxia, buffer-perfused, and subjected to 30 min of regional ischaemia and reperfused for 120 min. Infarct size was determined by triphenyl tetrazolium chloride staining. Hyperoxia significantly reduced infarct size. In normoxic controls 23.0 +/- 8.3% of the area at risk was infarcted, while in hyperoxic animals infarct size was 14.8 +/- 5.6% of the area at risk (P = 0.012). Exposure of rats to hyperoxia modifies the vasomotor response of isolated aortic rings, and reduces the infarct size of isolated rat heart. These novel aspects of hyperoxic treatment require further studies to explore the potential of its clinical application.

Cardiac troponin T (cTnT) is a highly sensitive and specific serum marker of irreversible cardiomyocyte injury. It is not clear whether cTnT also is a suitable marker of subtle, reversible injury. In the present investigation the relationship between cTnT release and function during the first 30 min of reperfusion after 30 min of global ischaemia, was investigated in isolated, retrogradely perfused rat hearts. Left ventricular systolic (LVSP), end-diastolic (LVEDP) and developed (LVDP) pressures, heart rate (HR), and coronary flow (CF) were measured. In one series of experiments (n=7) the kinetics of cTnT release during 30 min of reperfusion was investigated. An early, short-lasting peak of cTnT release appeared after 30 s of reperfusion. Then cTnT release gradually increased with a maximum after 20 min (from 0.08 +/- 0.03 before ischaemia to 2.16 +/- 0.40 ng min-1) (mean +/- SEM). In a second series of experiments (n=52) the relationship between cTnT release and cardiac function was investigated after 20 min of reperfusion. At this time point LVEDP increased (0 to 62 +/- 3 mmHg) and LVDP decreased (84 +/- 2 to 33 +/- 3 mmHg), but without any correlation with cTnT release. cTnT release was positively correlated to LVSP (P0.04, r=0.29), and negatively correlated to HR (P0.03, r=-0.31). cTnT concentration in the coronary effluent increased in parallel to increasing CF (P0.03, r=0.31). In conclusion, during the early reperfusion period there was no consistent correlation between cTnT release and dysfunction after global ischaemia in the isolated rat heart. Release of cTnT and post-ischaemic function appear to provide supplementary information in this particular model.

Ventricular fibrillation (VF) and ventricular tachycardia (VT) are common phenomena during reperfusion. In experimental research many hearts have to be excluded from haemodynamic evaluation because of severe arrhythmias. Theoretically, electroconversion or mechanical conversion (MC) might be used to convert VF or VT. MC induces a physical shock analogous to a chest thump. The aim of this study was to investigate the efficacy of MC in isolated, perfused rat hearts, and to see whether MC itself induced myocardial cell injury and functional impairment. Langendorff-perfused rat hearts (n = 89) from several experimental series subjected to 30 min of global ischaemia and 60 min of reperfusion were retrospectively analysed. Left ventricular systolic (LVSP), end-diastolic (LVEDP), and developed (LVDP) pressures, coronary flow (CF), and heart rate (HR) were measured. If VF or VT continued for 1 min during reperfusion, MC was attempted by a flick of the forefinger to the right ventricle. If VF or VT still occurred, MC was repeated. Hearts that did not have regular beating after 20 min of reperfusion were excluded. Release of cardiac troponin T (cTnT) was measured before ischaemia and after 20 min of reperfusion. Forty-four out of 89 hearts had VF or VT during reperfusion. Thirty-five hearts were converted, 18 of which were converted by one or two MCs only. The higher the total number of MCs employed, the more cTnT was released. After 20 min of reperfusion, LVEDP, LVDP and CF were better in hearts with a higher number of MCs and with increased release of cTnT. After 60 min of reperfusion, LVEDP was still improved in hearts with more cTnT release, whereas LVSP was lower, and LVDP and CF were independent of the number of MCs. There was no consistent correlation between release of cTnT and heart dysfunction. In conclusion, MC effectively converted VF or VT. MCs increased post-ischaemic myocardial cell damage, as judged from increased cTnT release. Post-ischaemic dysfunction was partly attenuated in hearts with multiple MCs, and did not correlate with release of cTnT. We feel that MCs should not be used in isolated, perfused hearts.

Objective: To compare the effects of ventilation with intermittent positive pressure and external high frequency oscillation by the Hayek Oscillator during the first 5 h after coronary artery bypass grafting. Methods: Eleven patients were randomized to intermittent positive pressure ventilation throughout the observation period (5 h), while 13 patients were initially ventilated with intermittent positive pressure ventilation, then by external high-frequency oscillations for 4 h, changing to positive pressure ventilation for the last hour. Results: Cardiac index, stroke volume index, right ventricular stroke work index, right ventricular end-diastolic volume index and mixed venous oxygen saturation were significantly increased during ventilation with external high-frequency oscillations, and arteriovenous oxygen content difference was significantly reduced. There were no significant inter- or intragroup differences in fluid accumulation, mean arterial blood pressure, arterial blood gases, pulmonary artery pressure. central venous pressure, pulmonary capillary wedge pressure, heart rate, systemic vascular resistance index, pulmonary vascular resistance index, intrapulmonary shunt fraction, right ventricular ejection fraction, right ventricular end-systolic volume index and left ventricular stroke work index. Conclusions: Ventilation by external high-frequency oscillations increases cardiac index and improves tissue perfusion. The increased pumping of the heart is probably caused by changes of the intracardiac pressure-volume relationship. The Hayek Oscillator may have distinct cardiovascular benefits as ventilatory assistance in postoperative cardiac surgical patients.

The effects of reactive oxygen species (ROS) on myocardial antioxidants and on the activity of oxidative mitochondrial enzymes were investigated in the following groups of isolated, perfused rat hearts. I: After stabilization the hearts freeze clamped in liquid nitrogen ( n = 7). II: Hearts frozen after stabilization and perfusion for 10 min with xanthine oxidase (XO) (25 U/l) and hypoxanthine (HX) (1 mM) as a ROS-producing system ( n = 7). III: Like group II, but recovered for 30 min after perfusion with XO + HX ( n = 9). IV: The hearts were perfused and freeze-clamped as in group III, but without XO + HX ( n = 7). XO + HX reduced left ventricular developed pressure and coronary flow to approximately 50% of the baseline value. Myocardial content of hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) increased at the end of XO + HX perfusion, indicating that generation of ROS and lipid peroxidation occurred. Levels of H 2 O 2 and MDA normalized during recovery. Superoxide dismutase, reduced glutathione and α -tocopherol were all reduced after ROS-induced injury. ROS did not significantly influence the tissue content of coenzyme Q 10 (neither total, oxidized, nor reduced), cytochrome c oxidase, and succinate cytochrome c reductase. The present findings indicate that the reduced contractile function was not correlated to reduced activity of the mitochondrial electron transport chain. ROS depleted the myocardium of antioxidants, leaving the heart more sensitive to the action of oxidative injury. Copyright © 1996 Elsevier Science Inc.

A model of cardiac dysfunction induced by reactive oxygen species (ROS) was established by adding hydrogen peroxide (H2O2) to the perfusate of isolated, Langendorff-perfused rat hearts, and the mechanism of functional injury was investigated. The following groups were included: 1 (n = 7), control perfusion; 2 (n = 11), perfusion with H2O2 (180 mumol 1(-1) for 10 min followed by recovery for 50 min; 3 (n = 4), control perfusion with N-acetylcysteine (NAC, 100 mumol 1(-1); 4 (n = 7), perfusion with H2O2 and NAC; 5 (n = 4), control perfusion with thiourea (15 mmol 1(-1), 6 (n = 7), H2O2 and thiourea together; 7 (n = 4), control perfusion with catalase (150 U ml-1); 8 (n = 7), catalase and H2O2, 9 (n = 4), control perfusion with deferoxamine (5 mmol 1(-1); and 10 (n = 7), deferoxamine and H2O2. coronary flow (CF), left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and heart rate (HR) were measured. All values are mean +/- SEM. When given alone, catalase, thiourea, NAC and deferoxamine did not influence left ventricular pressures, but NAC, catalase and thiourea increased CF. H2O2 increased CF (maximum 146 +/- 6% of baseline value after 5 min, p0.001 compared to group 1), decreased LVDP (minimum 14 +/- 5% of baseline value after 10 min, p0.0004), and increased LVEDP (from 0 mmHg to a maximum of 54 +/- 7 mmHg after 5 min recovery, p0.0003). All these changes gradually reversed during recovery. Catalase and thiourea both inhibited the H2O2-induced effects, but catalase inhibition was more complete. Neither NAC nor deferoxamine had any effect on H2O2-induced cardiac dysfunction. In conclusion, H2O2 perfusion is a convenient and reversible model of ROS-induced functional injury to isolated rat hearts. H2O2, rather than the hydroxyl radical, seems to be the main injurious ROS in this model.

Myocardial ischemia-reperfusion injury increases both tissue levels and release of histamine. To study the possible effects of ischemia-reperfusion on histamine metabolism tissue activities of histidine decarboxylase (HDC), histamine N-methyl transferase (HNMT) and diamine oxidase (DAO) were investigated in isolated rat hearts subjected to either 20 min global ischemia and 40 min reperfusion (n = 10) or control perfusion (n = 8). Histamine in the coronary effluent increased from 21 +/- 4 nmol/min (mean +/- SEM) before ischemia to 55 +/- 5 and 50 +/- 7 nmol/min after 4 and 10 min reperfusion (p0.004 and p0.004). Tissue HDC activity did not change during observation in any group. HNMT activity was unchanged in controls, but increased from 0.37 +/- 0.04 to 0.84 +/- 0.18 and 0.96 +/- 0.22 pmol methylhistamine/mg protein hour after 4 and 10 min reperfusion (p0.008 and p0.01). DAO decreased similarly in controls and ischemic-reperfused hearts during observation. In conclusion, the previously observed increase of tissue histamine during reperfusion cannot be explained by increased histamine synthesis or decreased histamine catabolism.

Leukocytes can take part in an inflammatory response in the heart after myocardial infarction or cardio-thoracic surgery. To investigate the injurious mechanism of activated polymorphonuclear leukocytes (PMN), isolated rat hearts were perfused with phorbol 12-myristate 13-acetate (PMA) activated PMN (3 x 10(6)/ml) alone for 10 min, in combination with a mixture of oxygen free radical scavengers (superoxide dismutase+catalase+thiourea) or in combination with ibuprofen (IBU), a cyclooxygenase inhibitor or diethylcarbamazine (DCM), a lipoxygenase inhibitor or BW 755C, a dual inhibitor of cyclooxygenase and lipoxygenase and an oxygen free radical scavenger. After 30 min of recovery, the hearts were perfusion-fixed with glutaraldehyde for electron microscopical examination. Based on examination of 25 micrographs per heart obtained by a random sampling procedure and on morphometric methods, volume fractions (Vv) of mitochondria (mito), altered mitochondria (alt mito), myofilament, and cellular edema were measured as fractions of myocyte volume. The most important finding was that Vv(alt mito/myocyte) was 0.09 +/- 0.16 and 0.02 +/- 0.04 in the hearts receiving PMN+PMA alone and when scavengers were added, respectively, whilst no changes in mitochondrial ultrastructure was observed after addition of IBU, BW 755C or DCM. Vv(mito/myocyte) was for PMN+PMA alone: 0.33 +/- 0.04, +scavengers: 0.29 +/- 0.02 +IBU:0.29 +/- 0.02, +BW 755C: 0.23 +/- 0.03*, +DCM: 0.28 +/- 0.02 (mean +/- S.D., *P0.05 compared to PMN+PMA). Capillary wall volume (cap wall) as a fraction of the whole capillary was also quantified. Vv(cap wall/cap) was for PMN+PMA alone: 0.26 +/- 0.06, +scavengers: 0.22 +/- 0.03, +IBU: 0.19 +/- 0.04*, +BW755C: 0.21 +/- 0.03, +DCM: 0.15 +/- 0.04* (*P0.05). These results further strengthen the notion that activated PMN are intravascularly active. In addition to exerting a cardiodepressive effect the present study shows that activated PMN can induce structural changes in the heart through the combined action of oxygen free radicals and arachidonic acid metabolites.

Histamine has inotropic, chronotropic, arrhythmogenic, and vasoactive effects, and is released from the heart in ischaemia-reperfusion injury. The effect of ventricular fibrillation (VF) and defibrillation (DEF) on histamine release was investigated in 9 anaesthetized patients undergoing transvenous implantation of ICD. Concomitant arterial and coronary sinus (CS) blood samples were drawn before induction of VF (duration 20 seconds), immediately after, and 2 and 5 min after DEF (18-24 Joules). Basal arterial histamine was 2.5 +/- 6 nmol/l, and did not increase after VF. The histamine level in CS was 1.1 +/- 0.2 nmol/l before VF (p0.008 compared to arterial), and increased to 2.5 +/- 0.6 nmol/l immediately after (p0.045 compared to basal), to 3 +/- 1.1 nmol/l 2 min after (p0.45), and to 2.4 +/- 0.8 nmol/l 5 min after VF. In the basal state there was an uptake of histamine across the coronary circulation. After VF/DEF the level of histamine increased in coronary venous blood, suggesting cardiac release of histamine.

Histamine is released from the heart during ischaemia-reperfusion injury. As histamine has cardiac effects, we investigated the role of histamine in ischaemia-reperfusion injury of isolated rat hearts. A Langendorff-model with 30 min global (37 degrees C) ischaemia followed by 60 min reperfusion was employed. The effects of ischaemia alone (n = 10, group 1.1 + n = 10, group 2.1, 2 different series), and ischaemia with H1- and H2-receptor blockade with cimetidine (10 microM, n = 10), chlorpheniramine (10 microM, n = 8), terfenadine (10 microM, n = 8), and promethazin (10 microM, n = 9), or both cimetidine and chlorpheniramine (n = 8), were studied. Histamine was measured in the coronary effluent and cardiac tissue of group 1.1. Release of histamine increased from 6.5 +/- 1 pmol min-1 before ischaemia to 19 +/- 3 pmol min-1 at the start of reperfusion. Ischaemia decreased left ventricular developed pressure to 18 +/- 11% (1.1) and 50 +/- 11% (2.1) of initial value (mean +/- SEM) at the start of reperfusion. Left ventricular end-diastolic pressure increased from 0 to 79 +/- 8 mmHg (1.1) and 39 +/- 9 (2.1) mmHg, while left ventricular systolic pressure was unchanged (101 +/- 12% in 1.1 and 101 +/- 10% in 2.1). Severe arrhythmias were induced in 90 (1.1) and 30 (2.1)% of the hearts, while coronary flow decreased during reperfusion. H2-blockade did not modify the changes in left ventricular pressures, coronary flow, or heart rate induced by ischaemia. Three different H1-blockers increased left ventricular systolic pressure, inhibited the decrease of developed pressure, attenuated the increase of end-diastolic pressure, and totally inhibited reperfusion arrhythmias. The effect of both blockers together was similar to that of H1-blockers alone. Coronary flow was increased during reperfusion in two of the groups with H1-blocker compared with ischaemic controls. Increased release of histamine from ischaemic-reperfused rat hearts concurred with depression of left ventricular function and arrhythmias during early reperfusion. Cardiac dysfunction during reperfusion was attenuated by three different H1-receptor blockers.

Release of histamine (H) by ischemia-reperfusion injury was investigated in isolated rat hearts (Langendorff model). The effect of 10, 15, 20, 25, 30, 40 and 60 min ischemia (n = 10 each) on H in the coronary effluent and in cardiac tissue was studied after 4 min reperfusion. Release of creatine kinase and lactate dehydrogenase in the coronary effluent increased with time of ischemia. Tissue H increased from 95 +/- 10 ng/g rat heart (mean +/- SEM) before ischemia to max 148 +/- 10 ng/g after 20 min ischemia (p0.002), and increased also after 15 (p0.01), 25 (p0.01), and 30 min (p0.045). H in the coronary effluent increased after 15 (from 16 +/- 3 to 26 +/- 2 pmol/min, p0.044), 30 (26 +/- 6 pmol/min, p0.027), and 60 min ischemia (47 +/- 6 pmol/min, p0.0044). Release of H during ischemia-reperfusion is neither dependent on the severity of the ischemic insult, nor on the level of tissue H.

Secretion of immunoreactive atrial natriuretic factors (ANF) after injury by ischaemia-reperfusion and toxic oxygen metabolites (TOM) was investigated in the following groups of Langendorff-perfused rat hearts: 1.1., control perfusion; 1.2., hearts perfused with H2O2 (200 mumol l-1) as a TOM-generating agent for 10 min, followed by recovery for 30 min; 1.3., thiourea (10 mmol l-1), a hydroxyl radical scavenger, was given together with H2O2; 2.1., control perfusion; 2.2., ischaemia (37 degrees C) for 20 min followed by reperfusion for 40 min. Ischaemia-reperfusion and TOM temporarily decreased left ventricular developed pressure and increased left ventricular end-diastolic pressure. The cardiac effects of H2O2 were inhibited by thiourea. Coronary flow (CF) was increased by TOM and decreased by ischaemia-reperfusion. Immunoreactive ANF was measured sequentially in the coronary effluent by radioimmunoassay. Basal secretion of immunoreactive ANF for all groups pooled was 0.45 +/- 0.02 pmol min-1 (mean +/- SEM), and did not change significantly with time in any group. In conclusion, ischaemia-reperfusion and TOM do not influence secretion of immunoreactive ANF.

Histamine is synthetized in the heart, and released by ischemia-reperfusion injury in several species. Histamine has arrhythmogenic, chronotropic, inotropic and vasoactive effects. Cardiac histamine release during ischemia-reperfusion may be mediated by toxic oxygen metabolites. We studied the effect of ischemia-reperfusion and toxic oxygen metabolites on release and synthesis of histamine in the isolated rat heart (Langendorff model). The following groups were included: I, (n = 10) control perfusion for 60 min; II, (n = 7) H2O2 (200 microM) was given for 10 min followed by 50 min recovery; III, (n = 7) thiourea (15 mM) was given in addition to H2O2; IV, (n = 7) thiourea given alone; V, (n = 7) catalase (150 U/ml) plus H2O2; VI, (n = 7) 20 min ischemia followed by 40 min reperfusion. The contents of histamine in the coronary effluent and in cardiac tissue were measured repeatedly (radioenzymatic method). Ischemia-reperfusion and toxic oxygen metabolites increased release of histamine in the coronary effluent. Concomitantly the histamine contents in cardiac tissue increased, indicating increased synthesis of histamine.

The metabolic function of the lungs may be impaired in acute lung injuries. The present work examined the effect of toxic oxygen metabolites (TOM) on the pulmonary clearance of prostaglandin E2 (PGE2). Isolated rat lungs perfused with plasma were exposed to TOM, generated by xanthine oxidase (XO) and hypoxanthine (HX) in the perfusate. Inactivation of PGE2 was determined by superfusion bioassay technique. XO and HX (n = 6) reduced the inactivation of PGE2 from 78 +/- 4% (mean +/- SE) to 61 +/- 3%. This reduction was inhibited by the free radical scavengers superoxide dismutase and catalase, as well as by allopurinol, an inhibitor of XO. Neither hydrostatic lung edema nor perfusion per se decreased the inactivation of PGE2. Lungs pretreated with indomethacin still showed impaired PGE2 inactivation after exposure to XO and HX, indicating that a possible release of PGE2-like substances did not influence our findings. This study indicates that TOM may impair pulmonary metabolic function as shown by reduced inactivation of PGE2.

Twenty patients accepted for coronary bypass surgery were randomized to receive either a concentrated ethylester compound of n-3 fatty acids, with a daily dose of 3.15 g of eicosapentaenoic acid (EPA) and 1.89 g of docosahexaenoic acid (DHA), or corn oil (controls) in a double blind study, to evaluate the effect on lipids, platelets and coagulation during the pre- and postoperative phase. Only patients with fasting triglyceride (TG) levels greater than or equal to 1.6 mmol/l at recruitment were eligible. The study was continued for 5 to 6 months. Surgery was usually performed at mid-intervention. Blood samples were collected during morning hours in fasting subjects, just prior to intervention, preoperatively and at final postoperative follow-up. Moreover, blood loss was accurately accounted for postoperatively. A threefold increase (p = 0.0001) of EPA was noted at pre- and postoperative follow-up. TG-levels were reduced 20 and 39%, respectively, in patients on n-3 fatty acids, reaching statistical significance at end of intervention (p = 0.034). TG-levels in controls remained largely unchanged. In patients on n-3 fatty acids, there was a statistically significant increase in serum total cholesterol preoperatively, but this change was no longer present at completion of the study. No significant changes were noted in platelet function, as judged by bleeding time, collagen induced platelet aggregation and release of TxB2 during aggregation. Parameters of extrinsic coagulation, including phospholipase C-sensitive factor VII (PLC-VII) and extrinsic pathway inhibitor (EPI), also remained essentially unchanged in both groups of patients. However, fibrinogen was significantly reduced in controls (p less than 0.05) at end of intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

A 30-year-old man presented with threatened rupture of an infrarenal aortic aneurysm. Clinical and laboratory investigations revealed no traumatic, atherosclerotic, infectious or inflammatory cause. Histologic examination of the aortic wall showed cystic degeneration of the media. Consequently the case could be classified as congenital abdominal aortic aneurysm in an adult.

Inhibitors of the arachidonic acid metabolism (AA) as well as scavengers of oxygen free radicals (OFR) have been shown to reduce myocardial infarct size. We investigated the effects of two inhibitors of AA metabolism on the cardiac effects of OFR. Isolated rat hearts were retrogradely perfused for 10 min with buffer containing hypoxanthine (HX, 1 mmol l-1) and xanthine oxidase (XOD: 24 U l-1) alone (n = 11), or with the addition of ibuprofen (IBU) (n = 6) (a cyclooxygenase inhibitor) or BW 755C (n = 6) (a dual inhibitor of cyclo-oxygenase and lipoxygenase). The hearts were observed for 30 min thereafter (total observation time 40 min). Left-ventricular pressures were measured by a balloon in the left ventricle. HX + XOD significantly reduced left-ventricular developed pressure (LVDP) and coronary flow (CF), but not heart rate. The reduction of LVDP and CF was not significantly ameliorated by the addition of IBU (7.6 x 10(-4) mol l-1) or BW 755C (2 x 10(-3) mmol l-1). OFR increased left-ventricular end-diastolic pressure (LVEDP) from (mean +/- SEM) 0 to 22 +/- 4 mmHg (10 min) and 30 +/- 5 mmHg (40 min). Upon addition of IBU, LVEDP increased from 0 to 24 +/- 8 mmHg and 17 +/- 6 mmHg at 10 and 40 min respectively. The addition of BW 755C almost completely inhibited the increase in LVEDP (1 +/- 1 mmHg and 3 +/- 3 mmHg at 10 min and 40 min). In conclusion, except for inhibition of OFR-induced diastolic dysfunction by BW 755C, neither BW 755C nor IBU appear to inhibit cardiac injury induced by OFR.

Extracorporeal membrane oxygenation was introduced as a supplement ot mechanical ventilation in the treatment of two patients with severe acute respiratory failure and as heart assist in one patient with acute refractory cardiac failure after open heart surgery. The system includes a membrane oxygenator and a roller pump. The whole circuit is coated with partially degraded heparin covalently bound to the surface (Carmeda Bioactive Surface), reducing the need of systemic heparinization to a minimum. In the first case of acute respiratory failure a veno-venous bypass was employed, with cannulas in the right atrium and the femoral vein. Given a blood flow through the circuit of 2.5 l/min, ventilator settings could be favourably reduced. The patient was weaned off the bypass system after six days, off the ventilator after 120 days, and recovered completely. In two cases the system served as partial venoarterial bypass, and blood was returned to the ascending aorta. A 31 year-old male victim of a smoke inhalation lung injury was on bypass for four and a half days. He recovered completely after another 17 days of mechanical ventilation. A 68 year-old man with pump failure after cardiac surgery needed extracorporeal support as heart assist for seven days. On the eighth day he was weaned off intra-aortic balloon-pumping as well. Unfortunately, he died of septicemia, with multiple organ failure, 13 days later. The heparin-coated extracorporeal membrane oxygenation system may represent a major advancement in the treatment of critically ill patients in need of cardiopulmonary assist.

Effects of toxic oxygen metabolites (TOM) on the pulmonary vascular bed and airways were studied in isolated, plasma-perfused rat lungs. TOM were generated by xanthine oxidase (XO) (0. 1 or 0. 25 unit– ml-1) and hyopxanthine (HX) (1 mol. l-1). In vitro measurements by chemiluminescence indicated that the major oxygen metabolite generated by XO and HX was H2O2. Measurements of Po2 in the perfusate as an indicator of O2–consumption suggested that production of TOM by XO and HX was finished, within 30 min. XO and HX induced an early dose-dependent bronchoconstriction and a late increase in transpulmonary pressure (Ptp). Pulmonary arterial pressure (Ppa) increased gradually and levelled off within 30 min with low-dose XO, but not with high-dose XO. As judged by weight increase of the lungs, interstitial edema occurred regularly. Allopurinol, an inhibitor of XO, blocked the lung responses caused by XO and HX. Catalase attenuated all lung responses induced by XO and HX, while superoxide dismutase had no effect. The hydroxyl radical scavenger dimethylsulfoxide abolished the increase in Ptp and attenuated the increase in Ppa, but did not consistently protect the lungs from edema development. This study shows that TOM induce vasoconstriction, bronchoconstriction and lung edema in plasma-perfused rat lungs, mainly due to generation of H2O2 and the hydroxyl radical.

The mitochondrial isoenzyme of aspartate aminotransferase showed only slight increases in serum of twentyseven patients after uncomplicated coronary bypass surgery, which contrasted the rapid and substantial increases in creatine kinase MB. In seven patients suffering perioperative infarction or serious complications, substantial increases in mitochondrial aspartate aminotransferase were detected and the elevations in creatine kinase MB were prolonged. Mitochondrial aspartate aminotransferase may appear as a specific marker of myocardial necrosis following coronary bypass surgery. The elevations of creatine kinase and creatine kinase MB were detected as early as 5 minutes after onset of coronary reperfusion and slightly higher activities were measured in coronary sinus blood than in systemic blood sampled simultaneously. Increases in mitochondrial aspartate aminotransferase, however, could first be measured 8 hours after reperfusion.

During the period 1970-86, 155 men and 24 women were operated on for abdominal aortic aneurysms at the University Hospital in Tromsø. Elective operations were performed in 76 patients with an operative mortality of 5 (7%), impending rupture in 49, of whom 14 died (29%) and ruptured aneurysms in 54 patients, of whom 33 (61%) died. There has been a substantial increase in the number of patients per year admitted with abdominal aneurysms, from an average of 4.5 during the years 1970-76 inclusive, to over 20 during the years 1984-86. Operative and early postoperative mortality have been reduced and there has been no death following elective operations during the last three years of the reported period. Mortality was 8% for impending rupture and 45% for ruptured aneurysms. Electively abdominal aortic aneurysms can be operated safely even in patients over the age of 80. Ruptured aneurysms, however, still carry a high operative mortality in patients over the age of 70.

We have used the right gastroepiploic artery as a viable jump graft to the distal right coronary artery in two patients. The first patient was a 37 year-old man with recurrent angina after coronary bypass surgery with three vein grafts eight years previously. The second patient was a man aged 45 with angina in New York Heart Association Class III to IV. In both cases coronary angiography revealed severe triple vessel disease with multiple proximal and distal occlusions or stenosis. Both internal mammary arteries were also used in the two patients to revascularize the LAD and circumflex systems. Thus, a complete revascularization was achieved by use of only viable arteries as conduits. Both patients recovered well and were free from angina. At present only the first patient has had a postoperative angiogram, which showed good patency of the gastroepiploic artery jump graft. If the long-term patency of this type of graft is similar to that of the internal mammary arteries, it is another suitable arterial conduit for revascularization of the ischemic myocardium.

Accumulation of complement factors has been found to occur in the myocardium after infarction. We studied the possibility that the complement activation product C3a des-Arg is trapped within the coronary circulation during reperfusion of the ischemic myocardium. In 11 patients undergoing routine coronary artery bypass grafting, arterial blood was sampled before, during and after cardiopulmonary bypass. Blood was drawn from the coronary sinus concomitantly with arterial blood sampling 5 and 30 min after release of the aortic cross-clamp (n = 10). From a preoperative value of 92 +/- 13 ng/ml, C3a des-Arg rose during CPB to a maximum of 1816 +/- 393 at the end of CPB. Following reperfusion for 5 min, C3a des-Arg was 1284 +/- 232 ng/ml in arterial and 1106 +/- 100 in coronary sinus blood, a significant difference (p less than 0.05). The amount of C3a des-Arg trapped in the heart at 5-min reperfusion showed positive correlation with its arterial concentration (p less than 0.05). No significant difference was found after 30 min of reperfusion. Complement activation products trapped in the heart in the early reperfusion period may play a pathogenetic role in myocardial ischemia-reperfusion injury.

Toxic oxygen metabolites (TOM) released from stimulated phagocytes and lung tissue have been shown to injure the pulmonary microcirculation. In the present study we evaluated microvascular injury caused by TOM in rat lungs perfused with plasma. The injury, as indicated by an increase in vascular permeability, was assessed by determining the fluid filtration rate (FFR) after paralysing the pulmonary vascular bed with papaverine (0.1 mg/ml). TOM were generated by adding xanthine oxidase (XO) (0.05-0.125 U/ml) and hypoxanthine (HX) (1 mmol/l) to the perfusate. FFR was measured before, 30 and 60 min after addition of XO and HX. The following interventions were done: 1. the H2O2-scavenger catalase, 2. substitution of the perfusate after 30 min, 3. BW 755 C, a combined lipoxygenase and cyclooxygenase inhibitor, and 4. indomethacin, a cyclooxygenase inhibitor. Addition of XO and HX caused FFR to increase from 14 +/- 4 mg/min (mean +/- s.e. mean) at the onset to 56 +/- 7 mg/min and 86 +/- 10 mg/min after 30 and 60 min, respectively. Replacing the perfusate with fresh plasma after 30 min caused a significant reduction in FFR at 60 min, from 86 +/- 11 mg/min to 58 +/- 10 mg/min. Catalase prevented the increase in FFR. Indomethacin and BW 755 C had no effect on the increase in FFR. We conclude that TOM induced a partly reversible increase in microvascular permeability of isolated rat lungs. From previous studies, the activity of XO was expected to cease after 30 min. Therefore it is suggested that secondary products of TOM propagate the lung injury. The increase in permeability was not mediated by arachidonic acid metabolites.

Ischemia-reperfusion activates polymorphonuclear leukocytes (PMN). Depletion of PMN has been shown to reduce the size of experimental myocardial infarction. We have studied whether PMN activated by phorbol myristate acetate (PMA) would depress function of the isolated rat heart, and if this effect was mediated by oxygen free radicals (OFR). Cells and/or drugs were added to the perfusate into the aortic cannula for 10 min, followed by a 30 min recovery period. Oxygen free radicals formation was verified by chemiluminescence (CL). PMA-activated PMN (n = 13) caused CL response of 27,493 +/- 5113 counts (mean +/- S.E.M.) and reduced left ventricular developed pressure (LVDP) to 30 +/- 9% and coronary flow (CF) to 49 +/- 7% of the baseline value at the end of the observation period. Addition of super-oxide dismutase (SOD) and catalase (CAT) (n = 11) reduced the CL response to 5623 +/- 806 counts, but did not influence either LVDP (36 +/- 15%) or CF (51 +/- 18%). Addition of thiourea (TU) to the activated cell suspension (n = 8) further reduced the CL response (3663 +/- 474 counts), and LVDP was 86 +/- 5% and CF was 87 +/- 3%. When TU + SOD + CAT was mixed with PMN + PMA (n = 11), the CL was almost abolished (117 +/- 21 counts) and LVDP was 73 +/- 8% and CF was 94 +/- 6%. When CF was reduced (n = 7) alike the CF reduction in the hearts receiving PMA + PMA, LVDP was not significantly changed at the end of the observation period (75 +/- 6%). Unactivated PMN (n = 8) caused minor response of LVDP and CF, similar to PMN + PMA + TU and PMN + PMA + SOD + CAT + TU. PMA alone (n = 8) was cardiotoxic and caused changes similar to PMN + PMA. This effect was not inhibited by scavengers (n = 6). The supernatant of the PMN + PMA suspension (n = 7) did not impair cardiac function, suggesting that no free PMA was available after mixing with PMN. We conclude that activated PMN in the coronary circulation depressed cardiac function and increased vascular resistance due to OFR production.

Local low-dose (200 rads) gamma-irradiation to both kidneys impaired the excretion of 3H-labeled tumor products and reduced the survival time of mice carrying carcinomas in the ascites form. Daily i.p. injections of cell-free ascites fluid into tumor-free mice for 3 weeks resulted in the death of 25 of 180 irradiated animals, with no deaths among 180 injected unirradiated controls. The only histologically visible effects of irradiation of the kidneys during ascites tumor growth or during i.p. injections of cell-free ascites fluid was a cloudy swelling of the tubular epithelium in the renal cortex together with excessive protein in the tubular lumens.

All records of 652 patients treated for blunt chest trauma at Ullevål Hospital, Surgical Department 3, during the period 1973-1981 were analyzed for factors predictive of prognosis. Mortality for the whole group was 7.7%. Age, blood pressure on admission, the number of fractured ribs, the need for blood transfusions and the need for artificial ventilation were the most important predictors of prognosis. Mortality increased significantly when at least two extrathoracic injuries were present (22.6%). Intrathoracic injuries did not increase mortality in cases of isolated thoracic injuries. Combined thoraco-abdominal injuries carried a high mortality (25%), especially when the injury had resulted in rupture of the diaphragm (57.1%). There were no sex-related differences. The majority of the patients could be handled adequately with oxygen support, chest drainage, physiotherapy and pain relief. The incidence of bronchial infection, septicaemia and hypercoagulability was significantly higher for patients on ventilators than for patients breathing spontaneously. Mortality increased when septicaemia or bronchial infection was present (30.8 and 21.9%, respectively). The injury severity score (ISS) for the 50 patients who died in the hospital was similar to that of some other reports.

Experimental data show that lung injury may be prevented or reduced when steroids are administered early. It seems, however, difficult to reverse a lung injury which is already established. Accordingly, we have since 1976 administered high doses of methylprednisolone already on admission in patients with multiple rib fractures and/or flail chest (30 mg/kg i.v. X 3 at 8 hr intervals). A retrospective analysis of 143 patients with severe blunt chest trauma, most of whom were multitraumatized (72%) and many in shock (19%) revealed a significantly lower mortality for 44 steroid treated patients compared to 99 nonsteroid patients with similar injuries (9.1 vs 29.3%, p = 0.02). The incidence of bronchial infection and septicemia was not increased in steroid treated patients. There was also a lower incidence of multiple organ failure in the steroid treated group (4.5%) as compared to the control group (9.1%, n.s.). Hemodynamic and blood gas changes were examined in a prospective controlled study including 40 patients with multiple rib fractures and lung contusion. Pulmonary vascular resistance (PVR), which is a good parameter of injury severity, was reduced significantly in the steroid treated group. This led to a reduction in right heart work. The corticosteroid induced reduction in PVR was seen whether the patient was on a ventilator or breathed spontaneously. There were no significant differences in the a-v oxygen difference or in intrapulmonary shunting. Both the number of complications and the duration of artificial respiration were reduced in the steroid group.

Daily monitoring of the plasma proteolytic enzyme systems i.e. the coagulation, the fibrinolytic and the kallikrein-kinin system in multitraumatized patients with chromogenic substrate assays disclosed significant differences in the levels of Prekallikrein, Hageman Factor, Antithrombin-III, Prothrombin in survivors (N = 9) and fatal cases (N = 6) during the first week after admission. Since chromogenic peptide substrate assays are simple, cheap and easily automated, close monitoring of critical care patients may be rewarding.

Four patients aged 48-69 were operated upon for thoraco-abdominal aneurysms using a modified DeBakey technique reducing visceral ischemia to a minimum. The technique also pays attention to the preservation of the arterial supply to the spinal cord. All patients recovered and were discharged to their homes.

Effects of oxygen free radicals (OFR), enzymatically generated in the coronary circulation, were studied in isolated rat hearts retrogradely perfused with Krebs-Ringer solution. Control hearts (n = 6) functioned adequately for at least 5 hours. When rat hearts (n = 6) received xanthine oxidase (XOD) and hypoxanthine (HX) in order to generate OFR, survival time was reduced to 31 +/- 0.4 min (mean +/- SEM). Infusion of XOD (n = 8) or HX (n = 5) alone also reduced cardiac survival time, to 32 +/- 6 min and 139 +/- 23 min, respectively. When allopurinol (an inhibitor of XOD) was given together with XOD (n = 6), survival time (277 +/- 30 min) was similar to the control value. The production of OFR did not result in depressed coronary flow or heart rate, but reduced the aortic pulse pressure. OFR thus can depress cardiac function and may ultimately cause cardiac arrest.

Acid aspiration is followed by a moderate to severe fall in systemic arterial blood pressure, and it has been suggested that release from the lung parenchyma of vasoactive substances may be an important causal factor. We have tested this hypothesis by twice establishing cross circulation between one cat which received hydrochloric acid (4 ml/kg b.w., pH 1.5) intratracheally and another, untreated cat. Instillation of acid caused an immediate fall in heart rate and arterial blood pressure of the aspiration animal, suggesting a reflex inhibition of the heart triggered within the lung. Cross circulation with the untreated animal did not improve the situation of the aspiration animal; nor did it cause any change in arterial blood pressure or lung mechanics in the untreated animal, although most of the blood volumes of the two animals was exchanged. In a separate series of experiments including four cats, we investigated the relative advantages of various patterns of positive pressure ventilation in the treatment of the aspiration syndrome. Early onset of positive pressure ventilation (PPV) with a moderate positive end-expiratory pressure (PEEP) (+ 6 cmH2O) was an effective treatment. We conclude that local lung tissue injury with a secondary fall in estimated dynamic lung compliance and arterial pH and Po2 is the most important feature in the pathophysiology of aspiration.